The effects of glycine and MK-801 on hippocampal seizure threshold and
afterdischarge (AD) were determined in freely moving rats implanted with
intracranial electrodes. The 0.25 mg/kg (ip) dose of MK-801 significantly
reduced the primary hippocampal and cortical AD but induced neurological deficit
in 4 of 16 rats. The 0.25 mg/kg MK-801 dose also significantly increased the
seizure threshold as compared to the vehicle control treatment and reduced the
rebound cortical AD as compared to the control (nondrug) seizure response. The
40 mmol/kg (po) glycine dose significantly reduced the rebound hippocampal and
cortical AD without inducing neurological deficit. The 40 mmol/kg glycine dose
did not significantly alter the response to the ineffective 0.125 mg/kg MK-801
dose. These results demonstrate the differential effects of MK-801 and glycine
on primary and rebound hippocampal AD, respectively, which further establishes
the independence of the hippocampal seizure AD parameters. The lack of
interaction between MK-801 and glycine was unexpected considering that glycine
potentiates MK-801 receptor binding as well as the activity of other
anticonvulsants.

Glycine levels and receptor binding were measured in the medulla and spinal cord
of 2-month, 10-month, and 24-month-old Fischer 344 rats. The behavioral response
to the administration of the glycine antagonist, strychnine, was also evaluated
in 2- and 24-month-old animals to investigate the relevance of these
parameters to the susceptibility to seizures. Significant reductions in glycine in
both the spinal cord and medulla occurred from 2 to 24 months of age. The glycine
precursors, serine and threonine, were decreased only in the spinal cord.
[3H]Strychnine binding was also decreased by 38% and 34% in the medulla and
spinal cord, respectively, of 24-month-old rats compared to 2-month-olds.
[3H]GABA binding was similarly reduced while no age-related changes in
[3H]diazepam binding in the spinal cord were detected. Comparison of 2- and
24-month-old animals after systemic injection of 1.75 mg/kg strychnine showed
that senescent animals have a higher incidence of seizures and mortality
compared to young animals. Decreases in glycinergic neurotransmission may
lower strychnine seizure threshold in the aged animal.

The novel glycine-prodrug anticonvulsant, milacemide (2-N-pentylaminoacetamide)
(500 mg/kg), significantly increased (greater than 400% the seizure threshold
induced by hyperbaric oxygen (4.5 atmosphere). This effect was significantly
reduced by the selective inhibition of monoamine oxidase B by 1-deprenyl (2.0
mg/kg). 1-Deprenyl alone hardly affected the seizure threshold. These results
suggest that, in the brain, milacemide is oxidized to glycine and that this
reaction is mediated primarily by monoamine oxidase B. However, the interaction
of milacemide metabolites (glycine amide, pentanoate and glycine) as antagonists
of receptors of the glutamate NMDA (N-methyl-D-aspartate) subtype cannot be
excluded.

The effects of glycine and other inhibitory amino acid neurotransmitters on
strychnine convulsive threshold were studied in mice. The mean intravenous
threshold dose for strychnine to produce its convulsive effects in briefly
restrained mice was determined to be 1.386 +/- 0.035 mg/kg. The dose of
strychnine produced 100% postconvulsive mortality in all the mice tested.
Intraperitoneal administration of various doses (100-500 mg/kg) of glycine,
beta-alanine and L-threonine, 15-20 minutes prior to strychnine infusion
produced an increase of 13.92%, 25.73% and 17.15% respectively in strychnine
convulsive threshold in mice. Diazepam, known to produce its anticonvulsant,
sedative and muscle relaxant effects through its interaction either with central GABA or glycine receptors was found to be the most potent (48.39%) in increasing
strychnine convulsive threshold. Taurine and Baclofen were found to be
ineffective in raising strychnine convulsive threshold in mice. These
observations favor the possible use of either glycine or beta-alanine in
addition to diazepam in treating clinical cases of strychnine neurotoxicoses.

Prominent neurological abnormalities, including myoclonus, seizures, ataxia, and
hearing loss, have been noted in juvenile-onset biotin-responsive MCD. The
underlying defect in many of these patients, who generally present in the first
year of life, appears to be a deficiency of biotinidase. We have presented a
young woman with adult-onset myoclonus, ataxia, hearing loss, seizures,
hemianopia, and hemiparesis who responded to pharmacologic dosages of biotin.
Although she displayed many of the clinical and biochemical features of
juvenile-onset MCD, she did not have a biotinidase deficiency, and the
underlying defect remains to be determined. Because of her response to biotin,
we have advocated that other patients with unexplained myoclonus syndromes be
evaluated for biotin-dependent carboxylase deficiencies and undergo a
therapeutic trial with biotin.

Serum 24,25-dihydroxy vitamin D (24,25(OH)2D) and 25-hydroxy vitamin D (25-OHD)
concentrations and the ratio between the two were measured in 31 Israeli
children and adolescents receiving long-term treatment with phenobarbitone or
phenytoin and in controls. 24,25 (OH)2D concentrations were significantly
depressed in the patients, although the 25-OHD concentrations were similar to
those in the healthy controls. In four patients with radiological evidence of
osteopenia very low serum 24,25(OH)2D concentrations and serum 24,25(OH)2D:
25-OHD ratios were recorded. The findings suggest that 24,25(OH)2D deficiency
may play an important part in the pathogenesis of osteomalacia in patients
treated with anticonvulsant drugs and provide further indirect evidence that
24,25(OH)2D is important for normal bone structure.

Clinical signs that included lethargy, inappetence, diarrhea, and vomiting and
that progressed to seizures were observed in 40 feeder pigs that were
approximately 70 days old. The pigs were fed ground red wheat and whole milk and
were housed in a barn that did not allow exposure to direct sunlight. Analysis
of samples of feed obtained from the farm indicated inadequate quantities of
calcium and phosphorus as well as a low ratio of these 2 nutrients. Serum and
tissue concentrations of vitamin A were less than normal. Low serum calcium
concentrations, high serum phosphorus concentrations, and high alkaline
phosphatase and creatine kinase activities were compatible with low vitamin D
concentrations.

The pattern of hippocampal cell death has been studied following hippocampal
seizure activity and status epilepticus induced by 110-min stimulation of the
perforant pathway in awake rats. The order of vulnerability of principal cells
in the different hippocampal subfields--as determined by silver
impregnation--was found to be very similar to the pattern found in ischemia;
i.e., dentate hilus greater than CA1, subiculum greater than CA3c greater than
CA3a,b greater than dentate granule cells. The hilar somatostatin-containing
cells were the most vulnerable cell type, whereas all other subpopulations of
nonprincipal neurons--visualized by immunocytochemistry for the calcium binding
proteins parvalbumin and calbindin--were remarkably resistant. Pyramidal cells
in the CA3 region containing neither of the examined calcium binding proteins
were more resistant to overexcitation than CA1 pyramidal cells, most of which do
contain calbindin. This indicates that no simple relationship exists between
vulnerability in status epilepticus and neuronal calcium binding protein
content, and that local and/or systemic hypoxia during status epilepticus
may be responsible for the ischemic pattern of cell death.

We present a case of a one-month-old infant with hypocalcemia and rickets, with
symptoms of focal seizures. The ictal EEG showed left occipital spikes spreading
over all of the left hemisphere. From the laboratory studies, we concluded that
a low maternal circulating level of vitamin D would cause infantile hypocalcemia
and rickets, while immature renal response to parathyroid hormone and transient
hypoparathyroidism in infancy would induce hyperphosphatemia. Hypocalcemia may
be an important factor in the cause of focal seizures which start even
after the age of one month. Further, investigation of maternal vitamin D levels
should be done in infantile hypocalcemia.

Residents of an institution for the developmentally disabled in northwest Ohio
receiving anticonvulsant therapy for six months or more with phenobarbital or
phenytoin or both were studied for the prevalence of hypocalcemia and elevated
alkaline phosphatase level. Fifty-six residents were identified. Sixteen (29
percent) were hypocalcemic. Fifteen (27 percent) had elevated serum alkaline
phosphatase levels. Twenty-three residents received vitamin D supplementation
(400 IU/d) in addition to a normal dietary intake of calcium and vitamin D. The
mean serum calcium level was identical (8.65 mg/dL) for those receiving and not
receiving additional vitamin D. This study corroborates the findings of prior
studies suggesting an association between anticonvulsant usage and mineral and
bone abnormalities. The causal nature of this association, its clinical
significance, and its management require further investigation.

Electrical stimulation of the dorsal hippocampal formation of the rat was
employed to determine the effect of 1,25-dihydroxyvitamin D3 1,25-(OH)2D3), the
hormonal form of vitamin D, on induced seizure thresholds. Stereotaxic injection
of 100 micrograms or 50 micrograms 1,25-dihydroxyvitamin D3 in 2 microliter
propylene glycol into the hippocampus resulted in a significant elevation in
seizure threshold in all animals treated. 1,25-dihydroxyvitamin D3-induced
increases were noted within 5-10 min and lasted at least 120-180 min after
injection when the experiments were terminated. Intravenous injection of
1,25-(OH)2D3 also resulted in a significant elevation of seizure threshold;
however, the increase was transient, lasting only 30 min. This effect was
specific since 200 micrograms vitamin D3 or 200 micrograms 25-hydroxyvitamin D3
(25-(OH)D3), injected into the hippocampus, had no effect on seizure threshold
levels. This investigation represents the first direct demonstration of a role
for 1,25-(OH)2D3 in the regulation of seizure activity and suggests, along with
the previously demonstrated presence of immunoreactive vitamin D-dependent
calcium binding protein and receptors for 1,25-dihydroxyvitamin D3 in the brain,
that the vitamin D endocrine system may play a significant role in the
physiological mechanisms underlying convulsive disorders.

Department of Medicine, Boston University Medical Center, MA 02118, USA.
Vitamin D is absolutely essential for the maintenance of a healthy skeleton.
Without vitamin D, children develop rickets and adults exacerbate their
osteoporosis and develop osteomalacia. Casual exposure to sunlight is the major
source of vitamin D for most people. During exposure to sunlight, ultraviolet B
photons photolyze cutaneous stores of 7-dehydrocholesterol to previtamin D3.
Previtamin D3 undergoes a thermal isomerization to form vitamin D3. Increased
skin pigmentation, changes in latitude, time of day, sunscreen use, and aging
can have a marked influence on the cutaneous production of vitamin D3. Once
vitamin D3 is formed in the skin or ingested in the diet, it must be
hydroxylated in the liver and kidney to 1,25-dihydroxyvitamin D3
[1,25(OH)2D3].

It is now recognized that a wide variety of tissues and cells, both related to
calcium metabolism and unrelated to calcium metabolism, are target sites for
1,25(OH)2D3. 1,25(OH)2D3 stimulates intestinal calcium absorption and mobilizes
stem cells to mobilize calcium stores from bone. Noncalcemic tissues that
possess receptors for 1,25(OH)2D3 respond to the hormone in a variety of ways.
Of great interest is that 1,25(OH)2D3 is a potent antiproliferative and
prodifferentiation mediator. As a result, 1,25(OH)2D3 and its analogs have wide
clinical application in such diverse clinical disorders as rheumatoid and
psoriatic arthritis; diabetes mellitus type I; hypertension; cardiac
arrhythmias; seizure disorders; cancers of the breast, prostate, and colon; some
leukemias and myeloproliferative disorders; chemotherapy-induced hair loss; and
skin rejuvenation as well as skin diseases like psoriasis and ichthyosis.